We propose to evaluate a series of hypotheses relating specific aspects of energy balance, onecarbon metabolism, other dietary factors, and postmenopausal hormone use to breast cancer incidence, and to survival among women with breast cancer. We will also examine associations between functionally important polymorphisms and risk of breast cancer and potential interactions between specific genotypes and diet or hormones. This work will use the stored blood samples, archived DNA, repeated questionnaires, and the long follow-up in the Nurses' Health Study (1976- 2006). Exposures will also be related to tumor characteristics using pathology blocks that have already been collected from incident breast cancer cases. We will specifically examine intensity and duration of physical activity, body build before menarche, and plasma levels of adiponectin (an insulin sensitizer) in relation to breast cancer risk. We hypothesize that low availability of 1-carbon groups, assessed by dietary and/or blood levels of folate, vitamin B-12, choline, and methionine, and by reduced-activity genotypes of methylenetetrahydrofoiate reductase, are associated with breast cancers with a methylated BRCA-1 gene. We further hypothesize that breast cancer risk remains elevated among long term past users of combined estrogen plus progestin replacement therapy, and that polymorphisms in the ER and PR genes modify the relation between hormone use and breast cancer. Further, we hypothesize that dietary animal fat increases, and that vegetable fat, vegetables, fiber and walking reduces adverse outcomes after breast cancer. Because of the prospective design, long follow-up, and large number of cases, these analyses will provide important data for women and their health care providers attempting to reduce risk of breast cancer.